Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with appreciable morbidity and even mortality. Current treatment comprises non-specific immunosuppression with many serious side-effects. Furthermore, response to therapy is often incomplete. More specific, and less toxic therapies are thus required. Aberrant dendritic cell (DC) activation by immune complexes (IC) containing the prototypic autoantigens in SLE (DNA/protein or RNA/protein) bound to autoantibody is believed to play a key role in SLE pathogenesis. We have identified novel pathways involved in this DC activation by DNA/protein-containing IC. One major pathway involves IC engagement of Fc gamma receptor III on the DC surface, with subsequent delivery of DNA within the complex to intracellular Toll-like receptor 9 (TLR9). The application's objectives are to obtain a detailed understanding of the mechanisms and consequences of this interaction, and to determine whether a similar two receptor dual engagement mechanism applies to DC activation by RNA/protein-containing IC. Specific aim 1 compares the functional effects of DNA/protein and RNA/protein-containing IC on various DC subsets from wildtype, TLR9 deficient, TLR3 deficient, and various Fc gamma receptor deficient mice. Novel inhibitors will be tested for their ability to block this activation. Specific aim 2 compares Fc gamma receptor-mediated and Fc gamma receptor-independent uptake of antigen, particularly as regards delivery of antigen to TLR9-containing subcellular compartments. The consequences of this on T cell activation will be ascertained. In specific aim 3, the relative importance of TLR9-mediated DC activation (as compared to TLR9-mediated B cell activation) in SLE pathogenesis will be determined using DC adoptive transfer experiments, as well as by the development of mice in which TLR9 is specifically "knocked-out" in DC. It is anticipated that these studies will enhance the understanding of SLE pathogenesis and contribute to the development of new effective, safer and more specific therapies.